Effect of cranial irradiation on sperm concentration of adult survivors of childhood acute lymphoblastic leukemia: a report from the St. Jude Lifetime Cohort Study†.

STUDY QUESTION: Does lower dose (<26 Gy) cranial radiation therapy (CRT) used for central nervous system prophylaxis in acute lymphoblastic leukemia (ALL) adversely affect sperm concentration or morphology? SUMMARY ANSWER: CRT doses <26 Gy had no demonstrable adverse effect on sperm concentration or morphology. WHAT IS KNOWN ALREADY: Treatment with alkylating agents produces oligospermia and azoospermia in some patients. No prior study has been large enough to evaluate the independent effects of alkylating agents and lower dose (<26 Gy) CRT on sperm concentration or morphology. STUDY DESIGN, SIZE, DURATION: This cross-sectional study included male adult survivors of pediatric ALL who had received alkylating agent chemotherapy with or without CRT and who enrolled in the St. Jude Lifetime Cohort Study (SJLIFE) from September 2007 to October 2013. PARTICIPANTS/MATERIALS, SETTING,
METHODS: The inclusion criteria were males, ≥18 years of age, ≥10 years after diagnosis, treated at St. Jude Children's Research Hospital for ALL, and received alkylating agent chemotherapy. Semen analyses were performed on 173 of the 241 (78.1%) adult survivors of pediatric ALL who had received alkylating agent chemotherapy with or without CRT. Cumulative alkylating agent treatment was quantified using the cyclophosphamide equivalent dose (CED). Log-binomial multivariable models were used to calculate relative risks (RRs) and 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to those without CRT, risk of oligospermia or azoospermia was not increased for CRT <20 Gy (P = 0.95) or 20-26 Gy (P = 0.58). Participants 5-9 years of age at diagnosis compared to those 0-4 years of age (RR = 1.30, 95% CI, 1.05-.61) or those treated with 8-12 g/m2 CED (RR = 2.06, 95% CI, 1.08-3.94) or ≥12 g/m2 CED (RR = 2.12, 95% CI, 1.09-4.12) compared to those treated with >0 to <4 g/m2 CED had an increased risk for oligospermia or azoospermia. LIMITATIONS, REASONS FOR CAUTION: Our study relied on the results of one semen analysis. ALL survivors who did not participate in SJLIFE or who declined to submit a semen analysis may also have biased our results regarding the proportion with azoospermia or oligospermia, since those who provided a semen specimen were less likely to have previously fathered children compared to those who did not. The lower rate of previous parenthood among participants may have resulted in a higher observed frequency of azoospermia and oligospermia. WIDER IMPLICATIONS OF THE
FINDINGS: Treatment with <26 Gy CRT did not increase the risk of oligospermia or azoospermia, although a CED exceeding 8 g/m2 and an age at diagnosis of 5-9 years did increase risk of oligospermia and azoospermia. These findings can be used to counsel adult survivors of pediatric ALL. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Institutes of Health (grant numbers CA 21765, CA 195547, CA00874) and the American Lebanese Syrian Associated Charities (ALSAC). The authors have no competing interests to declare.